Nearly one in twenty women worldwide experience premenstrual symptoms severe enough to be classified as premenstrual dysphoric disorder (PMDD), however, PMDD's neurobiology is understudied. As women with PMDD cannot be distinguished from healthy controls by peripheral markers of ovarian function, it is critical that research is focused on the interaction between neuroactive steroids and the neurotransmitter systems they modulate. Progesterone's metabolite allopregnanolone (ALLO) is a powerful gamma- aminobutyric acid (GABAA) receptor agonist that, we and others propose, precipitates PMDD symptoms via interaction with brain regions such as the sexually dimorphic bed nucleus of the stria terminalis (BNST). The proposed research aims to examine how the fluctuating hormonal milieu of the menstrual cycle (MC) sets the stage for differences in stress and arousal reactivity between women with PMDD and healthy controls. Outcomes of interest include psychophysiologic (acoustic startle reflex; ASR) and HPA axis response to a laboratory stressor during the follicular and luteal phases of the MC and again after luteal phase administration of sertraline 50 mg/d. Exploration of the relationship between these primary outcomes and changes in ALLO across the MC and with SSRI treatment (PMDD group only) provides a novel approach to examining mechanism of action of SSRIs in the treatment of PMDD. The Neutral, Predictable, Unpredictable (NPU) threat of shock acoustic startle protocol is used herein to differentiate between anxiety-potentiated ASR (modulated by the BNST) versus fear-potentiated ASR (modulated by the amygdala), an important distinction when considering the development of new interventions for PMDD. We hypothesize that women with PMDD will have heightened baseline and anxiety-potentiated ASR, but not fear-potentiated ASR in the luteal phase compared to the follicular phase, and compared to female controls during the luteal phase. These findings would be consistent with preclinical studies showing that ALLO, which is co-released under conditions of stress and enhanced by SSRI administration, diminishes the impact of stress hormones on contextual fear or anxiety- potentiated (BNST related) ASR. We expect no between group differences or pre-post sertraline effects on fear-potentiated ASR (amygdala related). This research will further our understanding of the nature of PMDD and provide additional insights into the therapeutic action of SSRIs with the goal of fostering development of new interventions for the treatment of PMDD. This grant mechanism comes at a critical time in the candidate's career development as she integrates her background in stress biology with investigation of neurosteroids and psychophysiology, building toward a larger research program on the neuroendocrinology of PMDD and stress responsivity. The proposed research includes expert mentorship from Dr. Neill Epperson and input from an esteemed panel of co-mentors/advisors, and will advance the candidate's career towards independence in women's reproductive behavioral health.